(3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-oxo-9,10-secoestra-5,7-dien-17-yl]butanenitrile | 1010389-24-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子
• 英文名称: (3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-oxo-9,10-secoestra-5,7-dien-17-yl]butanenitrile
• CAS: 1010389-24-8
• 化学式: C₃₄H₅₉NO₃Si₂
• 分子量: 586.018
• InChiKey: VJFYDRLDZNRFDI-XJNLNMSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.75
• 重原子数：
  40.0
• 可旋转键数：
  7.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  59.32
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-oxo-9,10-secoestra-5,7-dien-17-yl]butanenitrile 、 甲基三苯基溴化膦 在 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 3.0h， 以94.2%的产率得到(3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylene-9,10-secoestra-5,7-dien-17-yl]butanenitrile
  参考文献：
  名称：

  2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism

  摘要：

  To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1 alpha-hydroxyvitamin D-3 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.09.017
• 作为产物：
  描述：

  (3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-9,10-secoestra-5,7-dien-17-yl]butanenitrile 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以96%的产率得到(3R)-3-[(1R,3R,7E)-1,3-bis{[tert-butyl(dimethyl)silyl]oxy}-2-oxo-9,10-secoestra-5,7-dien-17-yl]butanenitrile
  参考文献：
  名称：

  2-Methylene 19-nor-25-dehydro-1α-hydroxyvitamin D3 26,23-lactones: Synthesis, biological activities and molecular basis of passive antagonism

  摘要：

  To investigate the molecular mechanism of vitamin D receptor (VDR) antagonists having no structurally bulky group interfering with helix 12 of the ligand-binding domain of the VDR, we have synthesized four diastereomers at C(20) and C(23) of 19-nor-1 alpha-hydroxyvitamin D-3 25-methylene-26,23-lactone bearing a 2MD-type A-ring. All four analogs showed significant VDR affinity. Transactivation was tested by using Cos7 cells and HEK293 cells. In both types of cells, LAC67a showed little transactivation potency and inhibited the activation induced by the natural hormone concentration-dependently, indicating that LAC67a works as an antagonist for the VDR in these cells. LAC67b, LAC82a and LAC82b similarly acted as VDR antagonists in Cos7 cells, but in HEK293 cells they behaved as potent VDR agonists. Docking of four lactones into the VDR-LBD, followed by structural analysis, demonstrated that each lactone lacks the hydrophobic interaction with helix12 necessary for maintaining the active conformation of the VDR, indicating that these lactones are passive-type antagonists. Furthermore, each docking structure explained the characteristic transactivation profiles of the four lactones. On the basis of our present findings, we suggest that the ligand acts as an agonist if there are appropriate coactivators in the cells to bind to the looser VDR-ligand complex, and as an antagonist if there are no such appropriate coactivators. The molecular basis of the passive antagonism is discussed in detail. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.09.017